The inability to control blood glucose levels underlies a variety of metabolic conditions. Diabetes is a hyperglycemic syndrome that results from a defect in insulin secretion in response to glucose (type 1 and type 2 diabetes) and decreased insulin effectiveness in stimulating skeletal muscle glucose uptake and in restraining hepatic glucose production (type 2 diabetes). Diabetes it a highly prevalent disease and, although therapeutic options are available for some diabetics, there is an urgent need for additional therapies.
Fibroblast growth factor 21 (FGF21) is a member of the endocrine FGF subfamily, that includes FGF19 and FGF23, and it has been identified as a potential disease-modifying agent to reverse obesity and obesity-induced hepatosteatosis and hyperglycemia (see, e.g., Kharitonenkov and Larsen, Trends Endocrinol. Metab. 22(3):81-6 (2011); Kharitonenkov et al., J. Clin. Invest. 115: 1627-35 (2005); WO 2010/042747). The endocrine FGF21 protein binds to three FGF receptors (FGFRs 1-3), and improves insulin resistance and type 2 diabetes by these receptors together with their membrane bound co-receptor beta-Klotho. However, its development has been hampered by its poor pharmacokinetics and poor understanding of the biological mechanism of action. Anti-FGFR1 antagonist antibodies have also been proposed for the treatment of diabetes (WO 2005/037235). However, the identity of which of the three FGFRs mediates the beneficial metabolic activity of FGF21 has not been discovered.